Chronic Mountain Sickness (CMS) or Monge disease is characterized by severe hypoxemia, excessive polycythemia and accentuated pulmonary hypertension (PH). The pathogenic mechanism remains to be established. Recently we have identified two strains of Sprague Dawley rats: Upon chronic exposure to a simulated altitude of 18,000 ft, Hilltop (H) strain developed signs of CMS (severe polycythemia and severe PH) with high mortality rate from right heart failure whereas the Madison (M) strain tolerated the same conditions of hypoxic exposure with only moderate cardiopulmonary and hematological responses. Relative hypoventilation and enhanced pulmonary vasoreactivity which have been proposed as the cause for human CMS cannot explain the etiology of the severe PH and polycythemia in CMS in rats. We propose that the more severe polycythemia and hypervolemia in chronically hypoxic H rats contribute to the severe PH in CMS. Under severe hypoxia, polycythemia may represent an inappropriate response without compensatory significance in both strains of rats. Therefore, the primary factor determining susceptibility to CMS may be an exaggeration of this inappropriate polycythemic response in H rats. The objectives of this proposed study are: (1) to test the hypothesis that an exaggerated polycythemia and hypervolemia contribute to the severe PH in CMS in chronically hypoxic H rats by: a) determining the time course of the development of polycythemia, total blood volume and cardiopulmonary responses in fully awake animals during exposure to hypoxia in both H and M rats; b) seeing whether the severe PH in the H rats during hypoxic exposure are alleviated by reducing the polycythemia and/or hypervolemia; c) studying whether severe PH in the M rats during hypoxia are induced by increasing their polycythemic and hypervolemic responses; (2) to evaluate the mechanism responsible for the exaggerated polycythemic responses to hypoxia in the H relative to M rats by determining in both strains a) circulating erythropoietin concentration, b) in vitro and in vivo sensitivity of splenic and medullary erythropoiesis to erythropoietin; c) total erythroid precursor cell population and d) oxygen dissociation curves and P-50 of the blood; and (3) to define the compensatory significance and regulation of the polycythemic responses to chronic hypoxia by determining, during exposure to increasing level of hypoxia, the systemic oxygen transport, oxygen carrying capacity, Hct, SaO2, PaO2, PVO2 and plasma erythropoietin levels.